Throughout this application, various publications are cited. The disclosure of these publications is hereby incorporated by reference into this application to describe more fully the state of the art to which this invention pertains.
Carcinoma of the prostate ("prostate cancer") is one of the most common types of malignancy. Among men 50 years of age or older, 30% harbor foci of cancer within the prostate. Only 1% of these afflicted men will be properly diagnosed with prostate cancer each year, highlighting a discrepancy between the high incidence of disease as revealed at autopsy and the much lower incidence revealed clinically. In 1992, 134,000 men in the United States were diagnosed with prostate cancer, and 32,000 died from this disease. Of all men clinically diagnosed with prostate cancer, more than half die within 10 years, and more than two-thirds suffer local or systemic progression despite therapy. Recently, testing for serum prostate-specific antigen (PSA) has allowed earlier detection, but it is unclear what the natural progression of the disease is in patients with elevated PSA but without large tumor burdens.
For cancer confined to the prostate, primary radiation or radical prostatectomy have roughly equivalent efficacy. Recurrences can be treated with radiation for primary surgery and, with difficulty, surgery for primary radiotherapy. Metastatic prostate lesions predominantly go to bone and can be treated by decreasing the androgen level in the subject. This can be done chemically by blocking adrenal and gonadal androgen production with drugs, or surgically by castration (which does not actually block adrenal production). The observation that patients will respond to such hormonal manipulation for only 6 months or so and then worsen suggests that the metastatic prostate lesions can become androgen-independent. This suggestion is supported by the finding that cultured cell lines from prostatic carcinomas contain mixed clones. These mixed clones are of three types: androgen-dependent, which survive only in the presence of exogenous androgen; androgen-sensitive, which remain alive in the absence of androgen and proliferate in its presence; and androgen-independent, which can survive as well as proliferate in the absence of androgens.
Among subjects suffering from prostate cancer, a significant population display clinical androgen-independence, i.e., the presence of prostate cancer cells which continue to proliferate even after therapeutic elimination of androgens. Surgery to remove a prostate tumor mass often results in the removal of androgen-independent cells along with other types of cells. However, surgery alone is rarely effective in this regard, since at least some androgen-independent cells remain. Accordingly, there exists a strong--and unmet--need for methods of treating prostate cancer using pharmaceutical agents which specifically inhibit the proliferation of androgen-independent cancer cells.